The invention relates to compounds of the formula I 
in which
R1 is H, alkyl having 1-6 C atoms or benzyl,
R2 is R10, COxe2x80x94R10, COOR6, COOR10, SO2R6 or SO2R10,
R3 is H, Hal, OA, NHR10, N(R10)2, xe2x80x94NH-acyl, xe2x80x94O-acyl, CN, NO2, OR10, SR10, R2 or CONHR10,
R4 is H, xe2x95x90O, xe2x95x90S, C1-C6-alkyl or acyl,
R5 is NH2, H2Nxe2x80x94C(xe2x95x90NH) or H2Nxe2x80x94(Cxe2x95x90NH)xe2x80x94NH, where the primary amino groups can also be provided with conventional amino protective groups or can be mono-, di- or trisubstituted by R10, COxe2x80x94R10, COOR10 or SO2R10, or R6,
R7, R8 are each independently of one another absent or H,
R7 and R8 together are also a bond,
X, Y are each independently of one another xe2x95x90Nxe2x80x94, xe2x80x94Nxe2x80x94, O, S, xe2x80x94CH2xe2x80x94 or xe2x95x90Cxe2x80x94, with the proviso that at least one of the two definitions X, Y is xe2x95x90Nxe2x80x94, xe2x80x94Nxe2x80x94, O or S,
W, z are each independently of one another absent, O, S, NR1, C(xe2x95x90O), CONH, NHCO, C(xe2x95x90S)NH, NHC (xe2x95x90S), C (xe2x95x90S), SO2NH, NHSO2 or CAxe2x95x90CAxe2x80x2,
R6 is a mono- or binuclear heterocycle which has 1 to 4 N, O and/or S atoms and can be unsubstituted or mono-, di- or trisubstituted by Hal, A, xe2x80x94COxe2x80x94A, OH, CN, COOH, COOA, CONH2, NO2, xe2x95x90NH or xe2x95x90O,
R9 is H, Hal, OA, NHA, NAAxe2x80x2, NHacyl, Oacyl, CN, NO2, SA, SOA, SO2A, SO2Ar or SO3H,
R10 is H, A, Ar or aralkyl having 7-14 C atoms,
R11 is H or alkyl having 1-6 C atoms,
A, Axe2x80x2 are each independently of one another H or unsubstituted or mono-, di- or tri-R9-substituted alkyl or cycloalkyl, each of which has 1-15 C atoms and in which one, two or three methylene groups can be replaced by N, O and/or S,
Ar is unsubstituted or mono-, di- or tri-A-and/or R9-substituted mono- or binuclear aromatic ring system having 0, 1, 2, 3 or 4 N, O and/or S atoms,
Hal is F, Cl, Br or I and
m, n are each independently of one another 0, 1, 2, 3 or 4,
and the physiologically acceptable salts thereof.
Similar compounds are disclosed, for example, in WO 94/29273, WO 96/00730 and WO 96/18602.
The invention was based on the object of finding novel compounds with valuable properties, in particular those which can be used to produce pharmaceuticals.
It has been found that the compounds of the formula I and their salts have very valuable pharmacological properties while being well tolerated. In particular, they act as integrin inhibitors, inhibiting in particular the interactions of the xcex1v integrin receptors with ligands. The compounds show particular activity in the case of the integrins xcex1vxcex23 and xcex1vxcex25. The compounds are very particularly active as adhesion receptor antagonists for the vitronectin receptor xcex1vxcex23. This effect can be demonstrated, for example, by the method described by J. W. Smith et al. in J. Biol. Chem. 265, 11008-11013 and 12267-12271 (1990). B. Felding-Habermann and D. A. Cheresh describe, in Curr. Opin. Cell. Biol. 5, 864 (1993), the significances of the integrins as adhesion receptors for a wide variety of phenomena and pathological states, specifically relating to the vitronectin receptor xcex1vxcex23.
The dependence of the initiation of angiogenesis on the interaction between vascular integrins and extracellular matrix proteins is described by P. C. Brooks, R. A. Clark and D. A. Cheresh in Science 264, 569-71 (1994).
The possibility of inhibiting this interaction and thus initiating apoptosis (programmed cell death) of angiogenic vascular cells by a cyclic peptide is described by P. C. Brooks, A. M. Montgomery, M. Rosenfeld, R. A. Reisfeld, T. Hu, G. Klier and D. A. Cheresh in Cell 79, 1157-64 (1994).
Experimental demonstration that the compounds according to the invention also prevent adhesion of living cells to the appropriate matrix proteins and, accordingly, also prevent the adhesion of tumour cells to matrix proteins can be provided by a cell adhesion assay carried out in analogy to the method of F. Mitjans et al., J. Cell Science 108, 2825-2838 (1995).
P. C. Brooks et al. describe, in J. Clin. Invest. 96, 1815-1822 (1995), xcex1vxcex23 antagonists for controlling cancer and for treating tumour-induced angiogenic disorders. The compounds of the formula I according to the invention can therefore be employed as pharmaceutical agents, in particular for treating oncoses, osteoporoses and osteolytic disorders, and for suppressing angiogenesis.
Compounds of the formula I which block the interaction of integrin receptors and ligands such as, for example, of fibrinogen on the fibrinogen receptor (glycoprotein IIb/IIIa) prevent, as GPIIb/IIIa antagonists, the spread of tumour cells by metastasis. This is proved by the following observations: The spread of tumour cells from a local tumour into the vascular system takes place by formation of microaggregates (microthrombi) by the tumour cells interacting with blood platelets. The tumour cells are shielded by the protection in the microaggregate and are not recognized by the cells of the immune system. The microaggregates are able to become attached to vessel walls, facilitating further penetration of tumour cells into the tissue. Since the formation of microthrombi is mediated by fibrinogen binding to the fibrinogen receptors on activated blood platelets, the GPIIa/IIIb antagonists can be regarded as effective metastasis inhibitors.
Compounds of the formula I inhibit not only the binding of fibrinogen, fibronectin and Willebrand factor to the fibrinogen receptor of the blood platelets but also the binding of other adhesive proteins, such as vitronectin, collagen and laminin, to the corresponding receptors on the surface of various types of cells. They prevent, in particular, the development of blood platelet thrombi and can therefore be employed to treat thromboses, stroke, myocardial infarct, inflammations are arteriosclerosis.
The properties of the compounds can also be demonstrated by methods described in EP-A1 0 462 960. The inhibition of fibrinogen binding to the fibrinogen receptor can be demonstrated by the method indicated in EP-A1 0 381 033.
The platelet aggregation-inhibiting effect can be demonstrated in vitro by the method of Born (Nature 4832, 927-929, 1962).
The invention accordingly relates to compounds of the formula I according to claim 1 and/or their physiologically acceptable salts for producing a pharmaceutical for use as integrin inhibitors. The invention particularly relates to compounds of the formula I according to claim 1 and/or their acceptable salts in which R2 is camphor-10-sulfonyl for producing a pharmaceutical for controlling pathologically angiogenic disorders, tumours, osteoporosis, inflammations and infections.
The compounds of the formula I can be employed as pharmaceutical agents in human and veterinary medicine, for the prophylaxis and/or therapy of thrombosis, myocardial infarct, arteriosclerosis, inflammations, stroke, angina pectoris, oncoses, osteolytic disorders such as osteoporosis, pathologically angiogenic disorders such as, for example, inflammations, ophthalmological disorders, diabetic retinopathy, macular degeneration, myopia, ocular histoplasmosis, rheumatoid arthritis, osteoarthritis, rubeotic glaucoma, ulcerative colitis, Crohn""s disease, atherosclerosis, psoriasis, restenosis after angioplasty, viral infection, bacterial infection, fungal infection, in acute kidney failure and in wound healing to assist the healing processes.
The compounds of the formula I can be employed as substances with antimicrobial activity in operations where biomaterials, implants, catheters or heart pacemakers are used. They have an antiseptic effect in such cases. The efficacy of the antimicrobial activity can be demonstrated by the method described by P. Valentin-Weigund et al. in Infection and Immunity, 2851-2855 (1988).
The invention furthermore relates to a process for preparing compounds of the formula I according to claim 1 and salts thereof, characterized
a) in that a compound of the formula I is liberated from one of its functional derivatives by treatment with a solvolysing or hydrogenolysing agent,
or
b) in that a compound of the formula II 
in which R1, R3, R4, R5, R7, R8, R11, W, X, Y, Z, m and n have the meanings stated in claim 1, is reacted with a compound of the formula III
R2xe2x80x94L xe2x80x83xe2x80x83III 
in which
R2 has the meaning stated in claim 1, and L is Cl, Br, I, OH or a reactively esterified OH group,
or
c) in that an ester of the formula I is hydrolysed,
or
d) in that a radical R1 and/or R5 is converted into another radical R1 and/or R5,
and/or
e) in that a basic or acidic compound of the formula I is converted by treatment with an acid or base into one of the salts thereof.
The compounds of the formula I have at least one chiral centre and may therefore occur in a plurality of stereoisomeric forms. All these forms (for example D and L forms) and mixtures thereof (for example the DL forms) are included in formula I. The compounds according to the invention also include so-called prodrug derivatives, that is to say compounds of the formula I which have been modified with, for example, alkyl or acyl groups, sugars or oligopeptides and which are rapidly cleaved in the body to give the active compounds according to the invention.
The abbreviations mentioned hereinbefore and hereinafter represent:
All the radicals which occur more than once, such as, for example, A and Axe2x80x2, can be identical or different, that is to say are independent of one another, and this applies to the entire invention.
In the formulae above, alkyl is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-, 1,2,2-trimethylpropyl, heptyl, octyl, nonyl or decyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 3-menthyl. Cycloalkyl is, in particular, the radical of a bicyclic terpene, and the camphor-10-yl radical is very particularly preferred.
Alkylene is preferably methylene, ethylene, propylene, butylene, pentylene, also hexylene, heptylene, octylene, nonylene or decylene. Aralkyl is preferably phenylalkyl and is, for example, preferably benzyl or phenethyl.
Cycloalkylene is preferably cyclopropylene, 1,2- or 1,3-cyclobutylene, 1,2- or 1,3-cyclopentylene, 1,2-, 1,3- or 1,4-cyclohexylene, also 1,2-, 1,3- or 1,4-cycloheptylene.
COxe2x80x94A is alkanoyl or cycloalkanoyl and is preferably formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl or octadecanoyl.
Acyl is C1-C7-acyl and has 1, 2, 3, 4, 5, 6 or 7 C atoms and is preferably, for example, formyl, acetyl, propionyl, butyryl, trifluoroacetyl or benzoyl.
Preferred substituents for alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl are, for example, Hal, OA, NHA, NAAxe2x80x2, CN, NO2, SA, SOA, SO2A, SO2Ar and/or SO3H, in particular, for example, F, Cl, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.
Preferred substituents for Ar and arylene are, for example, A and/or Hal, OA, NHA, NAAxe2x80x2, CN, NO2, SA, SOA, SO2A, SO2Ar and/or SO3H, in particular, for example, F, Cl, hydroxyl, methoxy, ethoxy, amino, dimethylamino, methylthio, methylsulfinyl, methylsulfonyl or phenylsulfonyl.
One, two or three methylene groups in each of the radicals alkyl, alkylene, cycloalkyl, cycloalkylene, alkanoyl and cycloalkanoyl can be replaced by N, O and/or S.
Arxe2x80x94CO is aroyl and is preferably benzoyl or naphthoyl.
Ar is unsubstituted or preferably, as indicated, monosubstituted phenyl, specifically preferably phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-cyanophenyl, o-, m- or p-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p-methylthiophenyl, o-, m- or p-methylsulfinylphenyl, o-, m- or p-methylsulfonylphenyl, o-, m- or p-aminophenyl, o-, m- or p-methylaminophenyl, o-, m- or p-dimethylaminophenyl, o-, m- or p-nitrophenyl, furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2-chloro-3-methyl-, 2-chloro-4-methyl-, 2-chloro-5-methyl-, 2-chloro-6-methyl-, 2-methyl-3-chloro-, 2-methyl-4-chloro-, 2-methyl-5-chloro-, 2-methyl-6-chloro-, 3-chloro-4-methyl-, 3-chloro-5-methyl- or 3-methyl-4-chlorophenyl, 2-bromo-3-methyl-, 2-bromo-4-methyl-, 2-bromo-5-methyl-, 2-bromo-6-methyl-, 2-methyl-3-bromo-, 2-methyl-4-bromo-, 2-methyl-5-bromo-, 2-methyl-6-bromo-, 3-bromo-4-methyl, 3-bromo-5-methyl- or 3-methyl-4-bromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-tri-tert-butylphenyl, 2,5-dimethylphenyl, p-iodophenyl, 4-fluoro-3-chlorophenyl, 4-fluoro-3,5-dimethylphenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 2,4-dichloro-5-methylphenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 2-methoxy-5-methylphenyl, 2,4,6-triisopropylphenyl, naphthyl, 1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, benzothiadiazol-5-yl or benzoxadiazol-5-yl.
Ar is furthermore preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
Arylene has the same meanings as indicated for Ar with the proviso that a further bond from the aromatic system is linked to the nearest bonding neighbour.
Heterocycloalkyl is preferably 1,2-, 2,3- or 1,3-pyrrolidinyl, 1,2-, 2,4-, 4,5- or 1,5-imidazolidinyl, 1,2-, 2,3- or 1,3-pyrazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-oxazolidinyl, 1,2-, 2,3-, 3,4- or 1,4-isoxazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-thiazolidinyl, 2,3-, 3,4-, 4,5- or 2,5-isothiazolidinyl, 1,2-, 2,3-, 3,4- or 1,4-piperidinyl, 1,4- or 1,2-piperazinyl, furthermore preferably 1,2,3-tetrahydrotriazol-1,2- or -1,4-yl, 1,2,4-tetrahydrotriazol-1,2- or 3,5-yl, 1,2- or 2,5-tetrahydrotetrazolyl, 1,2,3-tetrahydrooxadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydro-oxadiazol-2,3-, -3,4- or -4,5-yl, 1,3,4-tetrahydro-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,4-tetrahydrothiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 1,2,3-thiadiazol-2,3-, -3,4-, -4,5- or -1,5-yl, 2,3- or 3,4-morpholinyl, 2,3-, 3,4- or 2,4-thiomorpholinyl.
R6 is a mono- or binuclear heterocycle, preferably 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl, 1,2,3-thiadiazol-4- or -5-yl, 2-, 3-, 4-, 5- or 6-2H-thiopyranyl, 2-, 3- or 4-4-H-thiopyranyl, 3- or 4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzofuryl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzthiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl.
The heterocyclic radicals can also be partly or completely hydrogenated.
R6 can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-dioxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridazinyl, hexahydro-1-, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The said heterocyclic radicals may also be substituted once, twice or three times by Hal, A, xe2x80x94COxe2x80x94 A, OH, CN, COOH, COOA, CONH2, NO2, xe2x95x90NH or xe2x95x90O.
R6 is very particularly 1H-imidazol-2-yl, thiazol-2-yl, 1H-benzimidazol-2-yl, 2H-pyrazol-2-yl, 1H-tetrazol-5-yl, 2-iminoimidazolidin-4-on-5-yl, 1-alkyl-1,5-dihydroimidazol-4-on-2-yl, pyrimidin-2-yl or 1,4,5,6-tetrahydropyrimidin-2-yl.
R11 is H or alkyl with 1-6 C atoms, preferably H.
Accordingly the invention particularly relates to those compounds of the formula I in which at least one of the said radicals has one of the preferred meanings stated above. Some preferred groups of compounds can be represented by the following part-formulae Ia to Ig which correspond to the formula I and in which the undefined radicals have the meanings stated for formula I, but in which
in Ia)
in Ib)
in Ic)
in Id)
in Ie)
in If)
in Ig)
The compounds of the formula I and the starting materials for preparing them are moreover prepared by methods known per se, as described in the literature (for example in the stardard works such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart), specifically under reaction conditions known and suitable for the said reactions. It is also possible for this purpose to make use of variants which are known per se but which are no mentioned in detail here.
The starting materials can, if required, also be formed in situ so that they are not isolated from the reaction mixture but immediately reacted further to give the compounds of the formula I.
Compounds of the formula I can preferably be obtained by liberating compounds of the formula I from one of the functional derivatives thereof by treatment with a solvolysing or hydrogenolysing agent.
Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but comprise in place of one or more free amino and/or hydroxyl groups corresponding protected amino and/or hydroxyl groups, preferably those which have an amino protective group in place of an H atom bonded to an N atom, especially those which have an Rxe2x80x2xe2x80x94N group in place of an HN group, in which Rxe2x80x2 is an amino protective group, and/or those which have a hydroxyl protective group in place of the H atom of a hydroxyl group, for example those which correspond to the formula I but have a group xe2x80x94COORxe2x80x3 in place of a group xe2x80x94COOH, in which Rxe2x80x3 is a hydroxyl protective group.
It is also possible for a plurality of identical or different protected amino and/or hydroxyl groups to be present in the molecule of the starting material. If the protective groups present are different from one another, they can in many cases be eliminated selectively.
The term xe2x80x9camino protective groupxe2x80x9d is generally known and refers to groups which are suitable for protecting (blocking) an amino group from chemical reactions but which can easily be removed after the required chemical reaction elsewhere in the molecule has been carried out. Typical groups of this type are, in particular, unsubstituted or substituted acyl, aryl, aralkoxymethyl or aralkyl groups. Since the amino protective groups are removed after the required reaction (or sequence of reactions), their nature and size are not otherwise critical; however, those with 1-20, in particular 1-8, C atoms are preferred. The term xe2x80x9cacyl groupxe2x80x9d is to be interpreted in the widest sense in connection with the present process. It embraces acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and, in particular, alkoxycarbonyl, aryloxycarbonyl and, especially, aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; aralkanoyl such as phenylacetyl; aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as POA; alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC, 2-iodoethoxycarbonyl; aralkyloxycarbonyl such as CBZ (xe2x80x9ccarbobenzoxyxe2x80x9d), 4-methoxybenzyloxycarbonyl, FMOC; arylsulfonyl such as Mtr. Preferred amino protective groups are BOC and Mtr, also CBZ, FMOC, benzyl and acetyl.
The amino protective group is eliminated, depending on the protective group used, for example with strong acids, preferably with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene- or p-toluenesulfonic acid. The presence of an additional inert solvent is possible but not always necessary. Suitable and preferred inert solvents are organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, also alcohols such as methanol, ethanol or isopropanol, and water. Mixtures of the abovementioned solvents are also suitable. TFA is preferably used in excess without addition of another solvent, and perchloric acid is used in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9:1. The reaction temperatures for the cleavage are preferably between about 0 and about 50xc2x0, preferably between 15 and 30xc2x0 (room temperature).
The BOC, OBut and Mtr groups can be eliminated, for example, preferably with TFA in dichloromethane or with approximately 3 to 5N HCl in dioxane at 15-30xc2x0, and the FMOC group can be eliminated with an approximately 5 to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30xc2x0.
Protective groups which can be removed by hydrogenolysis (for example CBZ or benzyl) can be eliminated, for example, by treatment with hydrogen in the presence of a catalyst (for example of a noble metal catalyst such as palladium, preferably on a support such as carbon). Suitable solvents in this case are those indicated above, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis is, as a rule, carried out at temperatures between about 0 and 100xc2x0 under pressures between about 1 and 200 bar, preferably at 20-30xc2x0 under 1-10 bar. Hydrogenolysis of the CBZ group takes place satisfactorily, for example, on 5 to 10% Pd/C in methanol or with ammonium formate (in place of hydrogen) on Pd/C in methanol/DMF at 20-30xc2x0.
Compounds of the formula I can preferably be obtained by reacting compounds of the formula II with compounds of the formula III. The starting compounds of the formula II and III are, as a rule, novel. However, they can be prepared by methods known per se.
In the compounds of the formula III, L is preferably Cl, Br, I or a reactively modified OH group such as alkylsulfonyloxy with 1-6 C atoms (preferably methylsulfonyloxy) or arylsulfonyloxy with 6-10 C atoms (preferably phenyl- or p-tolylsulfonyloxy).
The compounds of the formula II are, as a rule, reacted in an inert solvent in the presence of an acid-binding agent, preferably of an organic base such as triethylamine, dimethylaniline, pyridine or quinoline. It may also be beneficial to add an alkali metal or alkaline earth metal hydroxide, carbonate or bicarbonate or another salt of a weak acid of the alkali metals or alkaline earth metals, preferably of potassium, sodium, calcium or caesium.
The reaction time depends on the conditions applied and is between a few minutes and 14 days, and the reaction temperature is between about xe2x88x9230xc2x0 and 140xc2x0, normally between xe2x88x9210xc2x0 and 90xc2x0, in particular between about 0xc2x0 and about 70xc2x0.
Examples of suitable inert solvents are hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether (methylglycol or ethylglycol), ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids such as formic acid or acetic acid; nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, water or mixtures of the solvents mentioned.
It is furthermore possible to hydrolyse an ester of the formula I. This is preferably carried out by solvolysis or hydrogenolysis as indicated above, for example with NaOH or KOH in dioxane/water at temperatures between 0 and 60xc2x0 C., preferably between 10 and 40xc2x0 C.
It is furthermore possible to convert a radical R1 and/or R5 into another radical R1 and/or R5. In particular, it is possible to convert a carboxylic acid into a carboxylic ester.
A cyano group is converted into an amidino group by reaction with, for example, hydroxylamine and subsequent reduction of the N-hydroxyamidine with hydrogen in the presence of a catalyst such as, for example, Pd/C.
It is furthermore possible to replace a conventional amino protective group by hydrogen by eliminating the protective group by solvolysis or hydrogenolysis as described above, or by liberating an amino group protected by a conventional protective group by solvolysis or hydrogenolysis.
A base of the formula I can be converted with an acid into the relevant acid addition salt, for example by reacting equivalent amounts of the base and of the acid in an inert solvent such as ethanol and subsequently evaporating. Acids particularly suitable for this reaction are those which provide physiologically acceptable salts. Thus, it is possible to use inorganic acids, for example sulfuric acid, nitric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, sulfamic acid, also organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, for example formic acid, acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, lauryl sulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be used for isolating and/or purifying the compounds of the formula I.
On the other hand, an acid of the formula I can be converted by reaction with a base into one of its physiologically acceptable metal or ammonium salts. Suitable salts in this connection are, in particular, the sodium, potassium, magnesium, calcium and ammonium salts, also substituted ammonium salts, for example the dimethyl-, diethyl- or diisopropylammonium salts, monoethanol-, diethanol- or diisopropanolammonium salts, cyclohexyl, dicyclohexylammonium salts, dibenzylethylenediammonium salts, furthermore, for example, salts with arginine or lysine.
The compounds of the formula I contain one or more chiral centres and may therefore exist in racemic or in optically active form. Resulting racemates can be resolved mechanically or chemically by methods known per se into the enantiomers. Preferably, diastereomers are formed from the racemic mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as xcex2-camphorsulfonic acid. An advantageous enantiomer resolution also makes use of a column packed with an optically active resolving agent (for example dinitrobenzoylphenylglycine); an example of a suitable mobile phase is a hexane/isopropanol/acetonitrile mixture, for example in the ratio 82:15:3 by volume.
It is, of course, also possible to obtain optically active compounds of the formula I by the methods described above by using starting materials which are already optically active.
The invention furthermore relates to the use of the compounds of the formula I and/or the physiologically acceptable salts thereof for producing pharmaceutical compositions, in particular by non-chemical means. For this purpose they can be converted together with at least one solid, liquid and/or semiliquid excipient or ancillary substance and, where appropriate, in combination with one or more other active ingredients into a suitable dosage form.
The invention furthermore relates to pharmaceutical compositions comprising at least one compound of the formula I and/or one of the physiologically acceptable salts thereof.
These compositions can be used as pharmaceuticals in human or veterinary medicine. Suitable excipients are organic or inorganic substances which are suitable for enteral (for example oral), parenteral, topical administration or for administration in the form of an inhalation spray and which do not react with the novel compounds, for example water, vegetable oils, benzyl alcohols, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, petrolatum. Used for oral administration are, in particular, tablets, pills, coated tablets, capsules, powders, granules, syrups, solutions or drops, for rectal administration are suppositories, for parenteral administration are solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants, and for topical administration are ointments, creams or dusting powders. The novel compounds can also be lyophilized, and the resulting lyophilisates can be used, for example, for producing products for injection. The stated compositions can be sterilized and/or comprise ancillary substances such as lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to influence the osmotic pressure, buffer substances, colourants, flavourings and/or several other active ingredients, for example one or more vitamins. The sprays which can be used for administration as inhalation spray comprise the active ingredient either dissolved or suspended in a propellant gas or mixture of propellant gases (for example CO2 or chlorofluoro-carbons). In this case, the active ingredient is preferably used in micronized form, and it is possible for one or more additional physiologically tolerated solvents to be present, for example ethanol. Solutions for inhalation can be administered using conventional inhalers.
The compounds of the formula I and their physiologically acceptable salts can be used as integrin inhibitors for controlling diseases, in particular pathologically angiogenic disorders, thromboses, myocardial infarct, coronary heart disease, arteriosclerosis, tumours, inflammations and infections.
Compounds of the formula I according to claim 1 and/or their acceptable salts in which R2 is camphor-10-yl are preferred for controlling pathologically angiogenic disorders, tumours, osteoporosis, inflammations and infections.
In this connection it is possible for the substances according to the invention to be administered, as a rule, in analogy to other known and commercially available peptides, but especially in analogy to the compounds described in U.S. Pat. No. 4,472,305, preferably in dosages between about 0.05 and 500 mg, in particular between 0.5 and 100 mg per dosage unit. The daily dose is preferably between about 0.01 and 2 mg/kg of body weight. The specific dose for each patient depends, however, on a wide variety of factors, for example on the activity of the specific compound employed, on the age, body weight, general state of health, sex, on the diet, on the time and route of administration, on the rate of excretion, combination of medicinal substances and severity of the particular disorder for which the therapy is applied. Parenteral administration is preferred.
All temperatures hereinbefore and hereinafter are stated in xc2x0 C. In the following examples, xe2x80x9cusual workupxe2x80x9d means: if necessary, water is added, if necessary, depending on the constitution of the final product, the pH is adjusted to between 2 and 10, extraction is carried out with ethyl acetate or dichloromethane, and the organic phase is separated off, dried over sodium sulfate, evaporated and purified by chromatography on silica gel and/or by crystallization.
Mass spectrometry (MS): EI (electron impact ionization) M+
FAB (fast atom bombardment) (M+H)+